Sustained release drug delivery devices

ABSTRACT

The present invention is directed to an improved sustained release drug delivery device comprising a drug core, a unitary cup, and a permeable plug.

FIELD OF THE INVENTION

[0001] The present invention relates to an improved device and methodfor delivering drug directly to the interior portions of the body of amammalian organism, such as to the eye. The method includesadministration of an agent effective in obtaining a desired diagnosticeffect or local or systemic physiological or pharmacological effect byinserting in a desired location in the body of a mammalian organism asustained release drug delivery device.

BACKGROUND

[0002] Over the years, various drugs have been developed to assist inthe treatment of a wide variety of ailments and diseases. However, inmany instances such drugs are not capable of being administered eitherorally or intravenously without the risk of various detrimental sideeffects.

[0003] CMV retinitis is a disease that is characterized by inflammationof the retina caused by infection with cytomegalovirus. CMV retinitis isone of the most common causes of sight-threatening infections amongpeople with HIV. The symptoms include loss of visual acuity, blindspots, and the loss of peripheral vision. Left untreated, CMV retinitiscan lead to blindness.

[0004] Intravenous ganciclovir (GCV) is effective in the treatment ofCMV retinitis in AIDS patients, but bone marrow toxicity limits itsusefulness. Continuous maintenance GCV therapy is necessary to preventprogression or recrudescence of the disease, but despite maintenancetherapy a significant number of patients experience a relapse duringtreatment. Additionally, there are other risks and problems associatedwith systemic GCV administration.

[0005] Intravitreal GCV injections administered once or twice weeklyhave resulted in temporary remission of CMV retinitis in AIDS patients.Intravitreal GCV injections may provide a higher intraocular drugconcentration than systemic therapy and reduce the incidence ofneutropenia. However, current treatment of CMV retinitis in AIDSpatients is clearly suboptimal. Ganciclovir is virustatic and thusdisease inhibition requires maintenance drug administration.

[0006] A more detailed explanation of the use of intravenous of GCV andintravitreal injections of GCV can be found in U.S. Pat. No. 5,902,598,herein incorporated in its entirety by reference. A discussion of thedifficulties associated with the systemic therapy of cyclosporine A inthe treatment of uveitis can be found in U.S. Pat. Nos. 5,773,019 and6,001,386, herein incorporated in their entirety by reference.

[0007] Accordingly, there exists a strong need for the elimination ofthe undesirable physiological problems associated with GCV treatment ofCMV retinitis, while maintaining the advantageous properties of thistreatment. Although delivering the drug locally with injections mayminimize the systemic toxicity of GCV, repeated injection is not apractical mode of administration.

[0008] Due to the risks that certain drugs impose, researchers havedeveloped systems for administering such drugs to aid in the treatmentof these ailments and diseases. A general discussion of drug deliverycontrol systems is provided in Controlled Drug Delivery (Part I), XueShen Wu, Ph.D. pp32, 33, 44-46, 63, 66, and 67 (Technomic Publishing Co.Inc., 1996), the entire contents of which are incorporated herein byreference. The systems have been designed largely to reduce and tocontrol the release rate of incorporated drugs. However, these systemsfail to achieve the advantages claimed by the present invention.

[0009] For example, U.S. Pat. No. 4,014,335 to Arnold, relates tovarious ocular inserts that act as a deposit or drug reservoir forslowly releasing a drug into the tear film for prolonged periods oftime. These inserts are fabricated as a three-layer laminate of flexiblepolymeric materials that are biologically inert, non-allergenic, andinsoluble in tear fluid. To initiate the therapeutic programs of thesedevices, the ocular inserts are placed in the cul-de-sac between thesclera of the eyeball and the eyelid for administering the drug to theeye. Multiple layer laminate systems can present a challenge toreproducibly manufacture and are more difficult to produce bylarge-scale manufacturing procedures.

[0010] The device of U.S. Pat. No. 3,416,530 is manufactured with aplurality of capillary openings that communicate between the exterior ofthe device and the interior chamber generally defined from a polymericmembrane. While the capillary openings in this construction areeffective for releasing certain drugs to the eye, they add considerablecomplexity to the manufacture of the device because it is difficult tocontrol the size of these openings in large-scale manufacturing usingvarious polymers.

[0011] U.S. Pat. No. 3,618,604 describes a device that does not involvesuch capillary openings, but instead provides for the release of thedrug by diffusion through a polymeric membrane. The device, as disclosedin a preferred embodiment, comprises a sealed container with the drugcontained in an interior chamber. Nonetheless, as described in U.S. Pat.No. 4,014,335, certain problems have been identified with such devicessuch as the difficult task of sealing the margins of the membrane toform the container. In addition, stresses and strains introduced intothe membrane walls from deformation during manufacturing of thosedevices may cause the reservoir to rupture and leak.

[0012] The above described systems and devices are intended to providesustained release of drugs effective in treating patients at a desiredlocal or systemic level for obtaining certain physiological orpharmacological effects. However, there are many disadvantagesassociated with their use, including the fact that it is often difficultto obtain the desired release rate of the drug.

[0013] The need for a better release system is especially significant inthe treatment of CMV retinitis. Thus, there remains a long-felt need inthe art for an improved device for providing sustained release of a drugto a patient to obtain a desired local or systemic physiological orpharmacological effect.

[0014] Prior to the development of the present invention, there wasdeveloped a drug delivery device that ameliorated many of the problemsassociated with sustained release drug delivery. The device, which isdisclosed in U.S. Pat. No. 5,378,475 (incorporated herein by referencein its entirety), included a first coating essentially impermeable tothe passage of the effective agent and a second coating permeable to thepassage of the effective agent. In the device, the first coating coveredat least a portion of the inner core; however, at least a small portionof the inner core is not coated with the first coating layer. The secondcoating layer essentially completely covers the first coating layer andthe uncoated portion of the inner core. The portion of the inner corewhich is not coated with the first coating layer allows passage of theagent into the second coating layer thus allowing controlled release.

[0015] While the devices described in U.S. Pat. No. 5,378,475 solve manyof the aforementioned problems pertaining to drug delivery, the devicesand the method of making the devices are not without some problems. Inparticular, polymers suitable for coating the inner core are frequentlyrelatively soft and technical difficulties can arise in production ofuniform films. This is especially true when attempting to coatnon-spherical bodies with edges (such as a cylindrical shape). In suchcases, relatively thick films must be applied to achieve uninterruptedand uniform coatings, which adds significant bulk to the device. Thus,the devices tend to be larger than necessary as a result of thethickness needed to seal the ends of the inner core. In addition toadding bulk, multiple layer devices are more difficult to manufacturereproducibly and are more difficult to produce by large-scalemanufacturing procedures. Often devices such as these require manualassembly that is time consuming, limits available supply, and addsvariability.

[0016] U.S. Pat. No. 5,902,598 also presents solutions to some of theproblems associated with manufacturing small devices. The device in U.S.Pat. No. 5,902,598 includes a third permeable coating layer thatessentially completely covers the device. While the third coating layerimproves the structural integrity of the device and helps to preventpotential leakage, some manufacturing difficulties can limit scaled upmanufacturing. For example, consistent application of the outermostcoating layer and reproducibility in manufacturing can be problems withdesigns which require manual assembly, a significant number of steps inthe assembly process, or outer dip coatings.

[0017] In addition, depending on the materials selected for theoutermost coating layer of the devices in U.S. Pat. Nos. 5,902,598 and5,378,475, there may exist a need to cure the entire device includingthe agent. Depending on the amount of curing required and the agentsused, in some applications this could result in undesirable degradationof the active.

[0018] The problem of device size is extremely important in the designof devices for implantation into the limited anatomical spaces such assmall organs like the eye. Larger devices require more complex surgeryto both implant and remove. The increased complexity can result incomplication, longer healing or recovery periods, and potential sideeffects (e.g. increased chance of astigmatism). Further, the extrapolymer required to achieve a uniform coating reduces the potentialinternal volume of the implant and hence limits the amount of drug thatcan be delivered, potentially limiting both efficacy and duration.

[0019] It would, therefore, be desirable to have a structurally stabledevice that can be reproducibly manufactured and manufactured bycommercial techniques. As a result of all of the above, there remains along felt need in the art for an improved device for providing sustainedrelease of a drug to a mammalian organism to obtain a desired local orsystemic physiological or pharmacological effect, especially for ocularuse.

SUMMARY OF THE INVENTION

[0020] The sustained release drug delivery device according to the firstembodiment of the present invention comprises:

[0021] a) a drug core comprising a therapeutically effective amount ofat least one agent effective in obtaining a diagnostic effect oreffective in obtaining a desired local or systemic physiological orpharmacological effect;

[0022] b) a unitary cup essentially impermeable to the passage of saidagent that surrounds and defines an internal compartment to accept saiddrug core, said unitary cup comprising an open top end with at least onerecessed groove around at least some portion of said open top end ofsaid unitary cup; and

[0023] c) a permeable plug which is permeable to the passage of saidagent, said permeable plug is positioned at said open top end of saidunitary cup wherein said groove interacts with said permeable plugholding it in position and closing said open top end, said permeableplug allowing passage of said agent out of said drug core, through saidpermeable plug, and out said open top end of said unitary cup.

[0024] In accordance with another embodiment of the present invention isa sustained release drug delivery device comprising:

[0025] a) a drug core comprising at least one agent effective inobtaining a diagnostic effect or effective in obtaining a desired localor systemic physiological or pharmacological effect;

[0026] b) a unitary cup essentially impermeable to the passage of saidagent that surrounds and defines an internal compartment to accept saiddrug core, said unitary cup comprising an open top end and at least onelip around at least a portion of said open top end of said unitary cup;and

[0027] c) a permeable plug permeable to the passage of said agentpositioned at said open top end of said unitary cup wherein said lipinteracts with said permeable plug holding it in position and closingsaid open top end, said permeable plug allowing passage of said agentout of said drug core, through said permeable plug, and out said opentop end of said unitary cup.

[0028] This invention is also directed to a method for providingcontrolled and sustained administration of an agent effective inobtaining a desired local or systemic physiological or pharmacologicaleffect comprising inserting in a desired location in the body of amammalian organism sustained release drug delivery devices of the firstand second embodiments of the present invention.

[0029] A method of manufacture of a sustained release drug deliverydevice according to the present invention comprises:

[0030] a) manufacturing a drug core comprising at least one agenteffective in obtaining a diagnostic effect or effective in obtaining adesired local or systemic physiological or pharmacological effect;

[0031] b) providing a unitary cup essentially impermeable to the passageof said agent that surrounds and defines an internal compartment toaccept said drug core, said unitary cup comprising an open top end withat least one recessed groove around at least some portion of said opentop end of said unitary cup;

[0032] c) inserting said drug core into said unitary cup; and

[0033] d) filling a material which is permeable to the passage of saidagent into said open top end of said unitary cup, allowing said materialto solidify thereby forming a permeable plug wherein said grooveinteracts with said permeable plug holding it in position and closingsaid open top end, said permeable plug allowing passage of said agentout of said drug core, through said permeable plug, and out said opentop end of said unitary cup.

[0034] The present invention is further directed to a method ofmanufacturing a sustained release drug delivery device comprising:

[0035] a) manufacturing a drug core comprising at least one agenteffective in obtaining a diagnostic effect or effective in obtaining adesired local or systemic physiological or pharmacological effect;

[0036] b) providing a unitary cup essentially impermeable to the passageof said agent that surrounds and defines an internal compartment toaccept said drug core, said unitary cup comprising an open top end withat least one lip extending around at least a portion of the said opentop end of said unitary cup;

[0037] c) inserting said drug core into said unitary cup; and

[0038] d) filling a material which is permeable to the passage of saidagent into said open top end of said unitary cup, allowing said materialto solidify thereby forming a permeable plug wherein said lip interactswith said permeable plug holding it in position and closing said opentop end, said permeable plug allowing passage of said agent out of saiddrug core, through said permeable plug, and out said open top end ofsaid unitary cup.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The drawings, which are not drawn to scale, are set forth toillustrate various embodiments of the invention. The drawings are asfollows:

[0040]FIG. 1 of the present invention is an enlarged cross-sectionalview down the center of one embodiment of the sustained release drugdelivery device showing a unitary cup with a lip extending inward aroundsome portion of the open top end of the cup, a permeable plug, the cupand plug acting as a reservoir for the drug core.

[0041]FIG. 2 of the present invention is an enlarged cross-sectionalview down the center of another embodiment of the sustained release drugdelivery device showing a unitary cup with a recessed groove around someportion of the inside of the open top end of the cup, a permeable plug,the cup and plug acting as a reservoir for the drug core.

[0042]FIG. 3 of the present invention is an enlarged top view of anotherembodiment of the sustained release drug delivery device showing aunitary cup with a plurality of lips extending inward around at least aportion of the open top end of the cup, a permeable plug, the cup andplug acting as a reservoir for the drug core.

[0043]FIG. 4 of the present invention is an enlarged cross-sectionalview down the center of another embodiment of the sustained release drugdelivery device showing a unitary cup with a plurality of lips and anintegral suture tab, a permeable plug, the cup and plug acting as areservoir for the drug core.

[0044]FIG. 5 is an enlarged top view of the embodiment of a sustainedrelease drug delivery device according to the present invention showingan lip extending outward around only a portion of the open top end ofthe cup.

[0045]FIG. 6 of the present invention is an enlarged cross-sectionalview down the center of another embodiment of the sustained release drugdelivery device showing a unitary cup with a plurality of grooves and anintegral suture tab, an impermeable plug with a passageway, a permeableplug, the cup and plugs acting as a reservoir for the drug core.

DETAILED DESCRIPTION OF THE INVENTION

[0046] The inventors have unexpectedly discovered a sustained releasedrug delivery device that because of its unitary cup and permeable plugdesign is structurally stabile and can be more easily and reproduciblymanufactured than current designs that are known in the art.

[0047] In one preferred embodiment, the device includes an impermeableunitary cup made of silicone with an integral suture tab, the unitarycup acts as a reservoir for a drug core containing an agent such asfluocinolone acetonide. A hole through the proximal end of the suturetab enables a suture to be used for securing the device. The open end ofthe unitary cup has lips extending inwardly around a portion of the topopen end of said cup. A permeable polymer solution of 10% polyvinylalcohol (PVA) is filled in the recess above the drug core. The PVAsolution is allowed to dry. The device is cured for 60 minutes at135-140° C. The PVA is sufficiently rigid to maintain its shape and theintegrity of the device and thereby forming a permeable plug such thatthe lips interact with the plug holding it in position and closing theopen top end. Together the cup with lips and the permeable plug act as areservoir surrounding the drug core and keeping it in place.

[0048] The expression “agent” as used herein broadly includes anycompound, composition of matter, or mixture thereof that can bedelivered from the device to produce a beneficial and useful result.

[0049] The term “impermeable” refers to a material that is sufficientlyimpermeable to environmental fluids as well as ingredients containedwithin the delivery device, such that the migration of such fluids andingredients into or out of the device through the impermeable materialis so low as to have substantially no adverse impact on the function ofthe device.

[0050] The term “permeable” refers to a material that is capable ofbeing passed through or permeated. Permeating includes passing throughopenings, holes, pores, or intersections.

[0051] The term “drug core” refers to any drug supply, drug depot, drugin suspension, reservoir or drug matrix. It includes one or more agentsnecessary to obtain the desired diagnostic effect or local or systemicphysiological or pharmacological effect. It includes any excipients,suspending agents, or binders. Reference may be made to any standardpharmaceutical textbook such as Remington's Pharmaceutical Sciences. Thedrug core can be in liquid form, solid form, in dispersion, or any otherform known in the art. Solid dose includes all conventional solid doseforms known in the art including tablets and pellets. Dispersionsinclude all conventional forms known in the art, such as liquid inliquid dispersions and solid in liquid dispersions.

[0052] The expression “passageway” as used herein includes an aperture,orifice, or bore sufficient to allow the agent to pass through. Thepassageway can be formed by mechanical procedures such as erosion,laser, or molding; and chemical procedures.

[0053] Referring to the drawing figures, like reference numeralsdesignate identical or corresponding elements throughout the severalfigures.

[0054] Turning now to the drawings in detail, which examples are not tobe construed as limiting, one embodiment of a device is indicated inFIG. 1. While the device shown in FIG. 1 is generally U like in shape,the cup can be any open container or bowl of any shape. FIG. 1 is across sectional view of a drug delivery device in accordance with thepresent invention. FIG. 1 includes an impermeable unitary cup 3containing a drug core 1 comprising an agent, the cup 3 has lips 4extending inward around the open top end 5 of the cup 3; and a permeableplug 2 formed of a material permeable to the passage of agent containedin the drug core 1. The permeable plug 2 is positioned in the recessbetween the top of the drug core 1 and below the lips 4 such that thelips 4 interact with the permeable plug 2 holding it in position andclosing the open top end 5 of the cup 3.

[0055] The lips 4 are the same impermeable material as the unitary cup 3and protrude inwardly from the top open end 5 of the cup 3. The cup 3and lips 4 are formed in a single unitary design to provide structuralintegrity to the device and facilitate manufacturing and handling. Thelips 4 are designed to hold the plug 2 in place during use. They canvary in size or shape. The lips 4 of the present invention include nubs,tabs, ridges, and any other raised or protruding member.

[0056] The permeable plug 2 can be formed in the unitary cup by fillingthe permeable material in the device in one step, such as injecting asolution of PVA. The permeable plug 2 can be formed to variousdimensional specifications which can be used to control diffusionproperties to achieve a desired release rate. For example, changing theamount of the permeable material filled into the cup can vary thethickness of the permeable plug. The same unitary cup and lips designcan be used for implants with a variety of release rates, making itpossible to use a single manufacturing line or type of equipment. Thus,the present invention allows for ease of construction by more standardmanufacturing techniques into devices with different release rates.

[0057] Together the cup 3 with lips 4 and the permeable plug 2 act as areservoir surrounding the drug core 1 and keeping it in place. The agentdiffuses out of the drug core 1, through the permeable plug 2, and outthe open top end 5. The permeable plug 2 has substantially the sameradial extent as the cup 3, so that the only diffusion pathway is out ofthe plug 2 and not around the sides 6. Glue or other adhesion means canbe employed to further bond the plug to the cup.

[0058] The invention further relates to a method for treating amammalian organism to obtain a desired local or systemic physiologicalor pharmacological effect. The method includes administering thesustained release drug delivery device to the mammalian organism andallowing the agent effective in obtaining the desired local or systemicphysiological or pharmacological effect to pass through the plug 2. Theterm “administering”, as used herein, means positioning, inserting,injecting, implanting, or any other means for exposing the device to amammalian organism. The route of administration depends on a variety offactors including type of response or treatment, type of agent, and thepreferred site of administration. However, the preferred method is toinsert the device into the target organ. In ocular applications, morepreferably through a surgical procedure followed by suturing the devicein place.

[0059]FIG. 2 illustrates an enlarged cross sectional view down thecenter of a sustained release drug delivery device in accordance withthe present invention. FIG. 2 includes an impermeable unitary cup 10containing a drug core 1 comprising an agent, the cup 10 has a recessedgroove 11 around the inside of the open top end 12 of the cup 10; and apermeable plug 2 formed of a material permeable to the passage of agentcontained in the drug core 1. The permeable plug 2 is positioned suchthat the groove 11 interacts with the permeable plug 2 holding it inposition and closing the open top end 12 of the cup 10.

[0060] Together the cup 10 with the groove 11 and the permeable plug 2act as a reservoir surrounding the drug core 1 and keeping it in place.The agent diffuses out of the drug core 1, through the permeable plug 2,and out the open top end 12. The permeable plug 2 has substantially thesame radial extent as the groove 11, so that the only diffusion pathwayis out of the plug 2 and not around the sides 6. Glue or other adhesionmeans can be employed to further bond the plug to the cup.

[0061]FIG. 3 is an enlarged top view of another exemplary embodiment ofa sustained release drug delivery device of the present invention. Theview in FIG. 3 is the top of a unitary cup comprising a plurality oflips 15 extending inwardly around the open top end of the cup. Thepermeable plug 2 is held in place by the lips 15 extending inwardlyaround the top open end of the cup.

[0062]FIG. 4 is a enlarged cross sectional view of a drug deliverydevice in accordance with the present invention. FIG. 4 includes animpermeable unitary cup 23 containing a drug core 1 comprising an agent,the cup 23 has lips 24, 25 extending inward around the open top end 20of the cup 23; and a permeable plug 2 formed of a material permeable tothe passage of agent contained in the drug core 1. The permeable plug 2is positioned in the recess between the top of the drug core 1 and thesecond lip 24 such that the lips 24, 25 interact with the permeable plug2 holding it in position and closing the open top end 20 of the cup 23.

[0063] The cup 23 further comprises an integral suture tab 21 with ahole 22 through the proximal end through which a suture can be placed toanchor the device to a structure of the organism requiring treatment.The proximal end of the suture tab is at the point of attachment, i.e.the point where the suture is attached. The preferred point ofattachment is at the end of the suture tab opposite the cup.

[0064] The location of the suture and the structure the device issutured to can be any that meet with current surgical techniques knownin the art, such as the sclera of the eye. Depending upon the locationof administration, the devices of the current invention may not requiresuturing in position.

[0065] Making the cup and suture tab in a single unitary design providesstructural integrity to the device, and facilitates manufacturing andhandling as one integral structure. In addition, by eliminating theassembly step of attaching the suture tab onto the cup, the singleunitary design decreases variability in the size and shape of thedevice.

[0066] Providing a suture hole 22 at the proximal end of the suture tabof the device enables the surgeon to attach the device withoutadditional steps. Providing the suture hole reduces the possibility oftearing the tab while passing the needle through during surgery. Somematerials, such as cured polyvinyl alcohol, are also very difficult tocreate a suture hole in once the device is assembled without causingcracks or breaks in the suture tab.

[0067] The devices of the present invention may comprise a plurality oflips. These lips can be on the same vertical plane, as illustrated inFIG. 3, or on a different vertical plane, as illustrated in FIG. 4. Thedevice may also be formed with any combination of lips in differentvertical planes suitable to hold the permeable plug in place. Forexample, a single lip may be placed in the top vertical plane (position24 in FIG. 4) and a plurality of lips, as in FIG. 3, at a lower verticalplane (position 25 in FIG. 4) positioned above the drug core tofacilitate holding the permeable plug in place. The function of the lipsis to hold the permeable plug in place and prevent failure of thestructural integrity of the device.

[0068] The devices of the present invention that employ recessed groovesto secure the permeable plug in place may also have a plurality ofgrooves in the same or different vertical planes as described above.

[0069]FIG. 5 is an enlarged top view of another exemplary embodiment ofa sustained release drug delivery device of the present invention. Theview in FIG. 5 is the top of a unitary cup comprising a single lip 30.The permeable plug 2 is held in place by the lip 30 extending inwardlyaround the top open end of the cup. The single lip can extend around theentire diameter of the top open end of the cup or extend around someportion, as illustrated in FIG. 5.

[0070]FIG. 6 illustrates an enlarged cross sectional view down thecenter of a sustained release drug delivery device in accordance withthe present invention. FIG. 6 includes an impermeable unitary cup 35containing a drug core 1 comprising an agent, the cup 35 has a pluralityof grooves 38,39 around the inside of the open top end 40 of the cup 35;an impermeable plug 36 with a passageway 37, and a permeable plug 2formed of a material permeable to the passage of agent contained in thedrug core 1. The impermeable plug 36 is positioned such that the groove39 interacts with the impermeable plug 36 holding it in position. Thepermeable plug 2 is positioned such that the groove 38 interacts withthe permeable plug 2 holding it in position and closing the open top end40 of the cup 35. Glue or other adhesion means can be employed tofurther bond the plugs to each other or the cup.

[0071] The impermeable plug of the embodiment in FIG. 6, can interactwith a groove, as illustrated, or be the same radial extent as the cup.An expanded recess groove could retain the impermeable plug and stillprovide an anchor groove for the permeable plug. The impermeable plugcan also be utilized in this manner in the unitary cup design thatcomprises a lip or lips. Due to elastic nature of some polymers, such assilicone, the same result could be achieved by essentially molding theimpermeable plug as part of the unitary cup and stretching thepassageway wide enough to insert the tablet or filling in a liquid orpowder drug core through the passageway.

[0072] In combination with the examples above, a variety of methods mayalso be utilized to provide adhesion of the permeable plug to theunitary cup portion of the device. These methods include the use ofadhesives, polymers such as PVA, or any other procedure known in the artto provide adhesion at the points of contact between the permeable plugand the unitary cup. The sealant can be permeable or impermeable to theagent or agents in the device depending upon the method and location ofapplication. If the adhesive is permeable to the beneficial agent, suchas in the case of a permeable polymer, it could be applied on top of thedrug core or directly to the permeable plug. The methods to improveadhesion will vary depending on the materials that the components aremanufactured from.

[0073] The above-described methods of adhesion may also be utilized toprovide adhesion of the impermeable plug to the unitary cup or permeableplug. For example, impermeable adhesives could be applied to only theedges of the impermeable plug and because the adhesive is present onlyon the edges, it improves the bond between the impermeable plug and thedevice without interfering with diffusion through the passageway(s) andthe permeable plug. If the adhesive is permeable to the beneficialagent, such as in the case of a permeable polymer, it could be appliedon top of the drug core, on top of the impermeable plug, or directly tothe impermeable plug before the impermeable plug is put into place.

[0074] The drug core or reservoir contains an agent effective inobtaining a desired local or systemic physiological or pharmacologicaleffect. The following classes of agents could be incorporated into thedevices of the present invention: anesthetics and pain killing agentssuch as lidocaine and related compounds and benzodiazepam and relatedcompounds; anti-cancer agents such as 5-fluorouracil, adriamycin andrelated compounds; anti-fungal agents such as fluconazole and relatedcompounds; anti-viral agents such as trisodium phosphomonoformate,trifluorothymidine, acyclovir, ganciclovir, DDI and AZT; celltransport/mobility impending agents such as colchicine, vincristine,cytochalasin B and related compounds; antiglaucoma drugs such asbeta-blockers: timolol, betaxolol, atenalol, etc; antihypertensives;decongestants such as phenylephrine, naphazoline, and tetrahydrazoline;immunological response modifiers such as muramyl dipeptide and relatedcompounds; peptides and proteins such as cyclosporin, insulin, growthhormones, insulin related growth factor, heat shock proteins and relatedcompounds; steroidal compounds such as dexamethasone, prednisolone andrelated compounds; low solubility steroids such as fluocinoloneacetonide and related compounds; carbonic anhydrize inhibitors;diagnostic agents; antiapoptosis agents; gene therapy agents;sequestering agents; reductants such as glutathione; antipermeabilityagents; antisense compounds; antiproliferative agents; antibodyconjugates; antidepressants; bloodflow enhancers; antiasthmatic drugs;antiparasiticagents; non-steroidal anti inflammatory agents such asibuprofen; nutrients and vitamins; enzyme inhibitors; antioxidants;anticataract drugs; aldose reductase inhibitors; cytoprotectants;cytokines, cytokine inhibitors, and cytokin protectants; uv blockers;mast cell stabilizers; and anti neovascular agents such asantiangiogenic agents like matrix metalloprotease inhibitors.

[0075] Examples of such agents also include neuroprotectants such asnimodipine and related compounds; antibiotics such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamycin, and erythromycin;antiinfectives; antibacterials such as sulfonamides, sulfacetamide,sulfamethizole,sulfisoxazole; nitrofurazone, and sodium propionate;antiallergenics such as antazoline, methapyriline, chlorpheniramine,pyrilamine and prophenpyridamine; anti-inflammatories such ashydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate,fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate,prednisolone acetate, fluoromethalone, betamethasone and triminolone;miotics and anti-cholinesterase such as pilocarpine, eserine salicylate,carbachol, di-isopropyl fluorophosphate, phospholine iodine, anddemecarium bromide; mydriatics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine; and prodrugssuch as those described in Design of Prodrugs, edited by Hans Bundgaard,Elsevier Scientific Publishing Co., Amsterdam, 1985. In addition to theabove agents, other agents suitable for treating, managing, ordiagnosing conditions in a mammalian organism may be placed in the innercore and administered using the sustained release drug delivery devicesof the current invention. Once again, reference may be made to anystandard pharmaceutical textbook such as Remington's PharmaceuticalSciences for the identity of other agents.

[0076] Any pharmaceutically acceptable form of such a compound may beemployed in the practice of the present invention, i.e., the free baseor a pharmaceutically acceptable salt or ester thereof. Pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate and the like.

[0077] A large number of polymers can be used to construct the devicesof the present invention. The only requirements are that they are inert,non-immunogenic and of the desired permeability. Materials that may besuitable for fabricating the device include naturally occurring orsynthetic materials that are biologically compatible with body fluidsand body tissues, and essentially insoluble in the body fluids withwhich the material will come in contact. The use of rapidly dissolvingmaterials or materials highly soluble in body fluids are to be avoidedsince dissolution of the wall would affect the constancy of the drugrelease, as well as the capability of the device to remain in place fora prolonged period of time.

[0078] Naturally occurring or synthetic materials that are biologicallycompatible with body fluids and eye tissues and essentially insoluble inbody fluids which the material will come in contact include, but are notlimited to, glass, metal, ceramics, polyvinyl acetate, cross-linkedpolyvinyl alcohol, cross-linked polyvinyl butyrate, ethyleneethylacrylate copolymer, polyethyl hexylacrylate, polyvinyl chloride,polyvinyl acetals, plasiticized ethylene vinylacetate copolymer,polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer,polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene, chlorinatedpolyethylene, poly(1,4′-isopropylidene diphenylene carbonate),vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethylfumerale copolymer, butadiene/styrene copolymers, silicone rubbers,especially the medical grade polydimethylsiloxanes, ethylene-propylenerubber, silicone-carbonate copolymers, vinylidene chloride-vinylchloride copolymer, vinyl chloride-acrylonitrile copolymer andvinylidene chloride-acrylonitride copolymer.

[0079] The device can be formulated in any convenient shape. Forexample, the device can be of any geometric shape dimensionally suitablefor insertion in the eye. Thus, the device can be ellipsoid,rectangular, round, etc. The shape of the cup in the present can beoptimized to provide a minimum profile for insertion.

[0080] The dimensions of the device can vary with the size of thedevice, the size of the core or reservoir, and the membrane thatsurrounds the core or reservoir. The targeted disease state, type ofmammalian organism, location of administration, and agents or agentadministered are among the factors which would effect the desired sizeof the sustained release drug delivery device.

[0081] The device according to the present invention may be made in avariety of ways. For example, if the unitary cup is going to be madeentirely of polymer, then the polymer can be injection molded or diecast into a desired shape and size. The permeable plug can also beformed by any conventional means depending on the materials selected.For example, the permeable plug can be formed by injecting, pouring,adding drop wise, or molding the permeable material. Depending on thepermeable material chosen, it may be required to dry and/or be cured toform the plug. The agent can be filled into the reservoir by anyconventional means such as drop-wise, syringe, or pipette. The agent canalso be made as a solid dose form such as a tablet or pellet and placedinto the unitary cup. For example, a standard size tablet could be usedwith varying compositions.

[0082] The preceding descriptions of how to make the device of thepresent invention is merely illustrative and should not be considered aslimiting the scope of the invention in any way. In particular, themethods of making the device depend on the identity of the agent.

[0083] The devices may be surgically implanted at or near the site ofaction. This is the case for devices of the present invention used intreatment of ocular conditions, primary tumors, rheumatic and arthriticconditions, and chronic pain. The devices may also be implantedsubcutaneously, intramusclarly, intraarterially, or intraperitoneally.This is the case when devices are to give sustained systematic levelsand avoid premature metabolism. In addition, such devices may beadministered orally.

[0084] Once in place, the device functions as a drug reservoir graduallyreleasing drug to the organ such as the eye and surrounding tissue. Thisdevice is particularly useful for treating ocular conditions such asglaucoma, proliferative vitreoretimopathy, diabetic retinopathy,uveitis, and keratitis. The device is also particularly useful as anocular device in treating mammalian organisms suffering fromcytomegalovirus retinitis wherein the device is surgically implantedwithin the vitreous of the eye.

[0085] As would be readily understood by one skilled in the art, thepreferred amounts, materials, and dimensions depend on the method ofadministration, the effective agent used, the polymers used, the desiredrelease rate and the like. Likewise, actual release rates and releaseduration depend on a variety of factors in addition to the above, suchas the disease state being treated, the age and condition of thepatient, the route of administration, as well as other factors whichwould be readily apparent to those skilled in the art. All of theforgoing U.S. Patents and other publications are expressly incorporatedby reference herein in each of their entities.

[0086] Thus, the devices of the present invention provide many importantadvantages over previously known sustained release drug deliverydevices. The unitary cup and plug design of the present inventionprovide an improved device that maintains its physical and chemicalintegrity in both the environments of use and in the presence of agentduring the controlled and continuous dispensing of agent over aprolonged period of time.

[0087] Forming the permeable plug in the unitary cup enables superiorinteraction with the lips or grooves of the unitary cup thereby lockingthe permeable plug in place. The resulting device has superiorstructural stability under the conditions of use.

[0088] Because of the structural integrity of the present design, theneed for coatings and multiple layers can be eliminated. For transportof agent out of the device and into the target area, it is onlynecessary that the permeable layer cover the portions of the device notcovered with the impermeable layer.

[0089] The unitary cup design and the use of plugs of the presentinvention result in a device that is more easily and reproduciblymanufactured then current designs known in the art. Manufacturing withthe single unitary cup and plugs minimizes the number of steps anddecreases potential variability in assembly. The present design alsoallows for mechanized manufacture. Eliminating manual assembly greatlydecreases the potential variability in the finished product.

[0090] Another advantage of the devices of the present invention is theease of construction by more standard manufacturing techniques intodevices with different release rates. The passageway in the impermeableplug allows for release of the agent. A single standard cup size can beused for multiple dosage configurations by varying the size or number ofpassageways in the impermeable plug, or by not using the impermeableplug at all. The permeable plug can also be made to various dimensionalspecifications that can be used to control diffusion properties toachieve a desired release rate. Thus, the same unitary cup can be usedfor implants with different release rates making it possible to use asingle manufacturing line or type of equipment.

[0091] In addition, the use of a single unitary cup and permeable plugto form the container or drug reservoir of the present design providesmore consistent and improved sealing capacity over the devices in theprior art. This permits the therapeutic program to be preciselycontrolled and the release of drug to be constant and predicted withaccuracy.

[0092] The ease of making the devices in the present invention minimizesstresses, strains, and deformations of the devices during manufacturewhich may cause the reservoir to rupture and leak. The leaking of agentcan result in harm to the patient and is a significant concern in themanufacture of implantable devices.

[0093] The following specific examples demonstrate sustained releasedrug delivery device designs of the present invention. However, it is tobe understood that these examples are for illustrative purposes only anddo not purport to be wholly definitive as to the conditions and scope.

EXAMPLE 1

[0094] A device according to the present invention is prepared. Theunitary cup is made of silicone and has eight inwardly extending lipsaround the top open end of the cup. The unitary cup has an integralsuture tab with a hole at the end of the tab opposite the cup. The drugcore is formed as a pellet composed of a 2.5 mg core of fluocinoloneacetonide and inserted into the cup. A 10% PVA solution is injected intothe unitary cup filling the recess between the drug core and the lips.The PVA is allowed to dry. The device is cured at 135-140° C. for 50minutes. The lips act to hold the permeable plug in place.

EXAMPLE 2

[0095] The device of example 1 above is placed in a vial with 2.0 mL ofa release media of 0.1 Sodium Acetate, pH 4.2. The vial is maintained ina 37° C. bath for 24 hours. After 24 hours, the vial is inverted toensure homogeneity and the device is removed to a new vial with freshmedia. This process is repeated for each day. The media is tested todetermine the amount of the drug and verifies that it is being releasedfrom the device. From the data that is collected, the release rate ofthe device can be determined.

EXAMPLE 3

[0096] A device according to the present invention is prepared. Theunitary cup is made of silicone and has two recessed grooves, one abovethe other, around the inside of the top open end of the cup. The firstgroove, which is the one further from the top open end of the cup, isdeeper then the second groove. The unitary cup has an integral suturetab with a hole at the end of the tab opposite the cup for suturing thedevice to a structure of a mammalian organism. The drug core is formedas a tablet composed of a 0.5 mg core of fluocinolone acetonide andinserted into the cup. An impermeable plug made of silicone, with apassageway in the center, is placed in the cup fitting into the firstgroove. A 10% PVA solution is filled into the unitary cup filling in therecess above the impermeable plug. The PVA is allowed to dry. The deviceis cured at about 140° C. for 50 minutes. The second groove interactswith the permeable plug holding it in place. From the foregoingdescription, one of ordinary skill in the art can easily ascertain theessential characteristics of the instant invention, and withoutdeparting from the spirit and scope thereof, can make various changesand/or modifications of the inventions to adapt it to various usages andconditions. As such, these changes and/or modifications are properly,equitably, and intended to be, within the full range of equivalence ofthe following claims.

1. A sustained release drug delivery device comprising: a) a drug corecomprising a therapeutically effective amount of least one agenteffective in obtaining a diagnostic effect or effective in obtaining adesired local or systemic physiological or pharmacological effect; b) aunitary cup essentially impermeable to the passage of said agent thatsurrounds and defines an internal compartment to accept said drug core,said unitary cup comprising an open top end with at least one recessedgroove around at least some portion of said open top end of said unitarycup; and c) a permeable plug which is permeable to the passage of saidagent, said permeable plug is positioned at said open top end of saidunitary cup wherein said groove interacts with said permeable plugholding it in position and closing said open top end, said permeableplug allowing passage of said agent out of said drug core, through saidpermeable plug, and out said open top end of said unitary cup.
 2. Thesustained release drug delivery device according to claim 1, whereinsaid unitary cup is made of polymer or metal.
 3. The sustained releasedrug delivery device according to claim 1, wherein said unitary cup ismade of silicone.
 4. The sustained release drug delivery deviceaccording to claim 3, wherein said permeable plug is made of PVA.
 5. Thesustained release drug delivery device according to claim 1, whereinsaid unitary cup further comprises a plurality of recessed groovesaround at least some portion of said open top end of said unitary cup.6. The sustained release drug delivery device according to claim 1,wherein said agent is a low solubility agent.
 7. The sustained releasedrug delivery device according to claim 1, wherein said agent isselected from a group consisting of immune response modifiers,neuroprotectants, corticosteroids, angiostatic steriods, anti-parasiticagents, anti-glaucoma agents, anti-biotics, anti-sense compounds,anti-angiogenic compounds, differentiation modulators, anti-viralagents, anti-cancer agents, and nonsteroidal anti-inflammatory agents.8. The sustained release drug delivery device according to claim 1,wherein said drug core comprises a plurality of agents.
 9. The sustainedrelease drug delivery device according to claim 1, further comprising animpermeable plug with at least one passageway positioned between saiddrug core and said permeable plug.
 10. A sustained release drug deliverydevice comprising: a) a drug core comprising at least one agenteffective in obtaining a diagnostic effect or effective in obtaining adesired local or systemic physiological or pharmacological effect; b) aunitary cup essentially impermeable to the passage of said agent thatsurrounds and defines an internal compartment to accept said drug core,said unitary cup comprising an open top end and at least one lip aroundat least a portion of said open top end of said unitary cup; and c) apermeable plug permeable to the passage of said agent positioned at saidopen top end of said unitary cup wherein said lip interacts with saidpermeable plug holding it in position and closing said open top end,said permeable plug allowing passage of said agent out of said drugcore, through said permeable plug, and out said open top end of saidunitary cup.
 11. The sustained release drug delivery device according toclaim 10, wherein said lip extends around the entirety of said open topend of said unitary cup.
 12. The sustained release drug delivery deviceaccording to claim 10, wherein said unitary cup comprises a plurality oflips at said open top end of said unitary cup.
 13. The sustained releasedrug delivery device according to claim 10, wherein said drug corecomprises an effective amount of a low solubility agent.
 14. Thesustained release drug delivery device according to claim 10, whereinsaid agent is selected from a group consisting of immune responsemodifiers, neuroprotectants, corticosteroids, angiostatic steriods,anti-parasitic agents, anti-glaucoma agents, anti-biotics, anti-sensecompounds, anti-angiogenic compounds, differentiation modulators,anti-viral agents, anti-cancer agents, and nonsteroidalanti-inflammatory agents.
 15. The sustained release drug delivery deviceaccording to claim 10, wherein said unitary cup is made of polymer ormetal.
 16. The sustained release drug delivery device according to claim10, wherein said unitary cup is made of silicone.
 17. The sustainedrelease drug delivery device according to claim 16, wherein saidpermeable plug is made of PVA.
 18. The sustained release drug deliverydevice according to claim 10, wherein said drug core comprises aplurality of agents.
 19. The sustained release drug delivery deviceaccording to claim 10, further comprising an impermeable plug with atleast one passageway positioned between said drug core and saidpermeable plug.
 20. A method for providing controlled and sustainedadministration of an agent effective in obtaining a desired local orsystemic physiological or pharmacological effect comprising inserting ina desired location in the body of a mammalian organism a sustainedrelease drug delivery device comprising; a) a drug core comprising atherapeutically effective amount of at least one agent effective inobtaining a diagnostic effect or effective in obtaining a desired localor systemic physiological or pharmacological effect; b) a unitary cupessentially impermeable to the passage of said agent that surrounds anddefines an internal compartment to accept said drug core, said unitarycup comprising an open top end with at least one recessed groove aroundat least some portion of said open top end of said unitary cup; and c) apermeable plug which is permeable to the passage of said agentpositioned at said open top end of said unitary cup wherein said grooveinteracts with said permeable plug holding it in position and closingsaid open top end, said permeable plug allowing passage of said agentout of said drug core, through said permeable plug, and out said opentop end of said unitary cup.
 21. The method according to claim 20,wherein said inserting step comprises inserting said sustained releasedrug device in a location selected from a group consisting of thevitreous of the eye, under the retina, and onto the sclera.
 22. Themethod according to claim 20, wherein said drug core comprises aplurality of agents.
 23. The method according to claim 20, wherein saidinserting step comprises injecting said sustained release drug deliverydevice at the desired location.
 24. A method for providing controlledand sustained administration of an agent effective in obtaining adesired local or systemic physiological or pharmacological effectcomprising inserting at a desired location in the body of a mammalianorganism a sustained release drug delivery device comprising; a) a drugcore comprising at least one agent effective in obtaining a diagnosticeffect or effective in obtaining a desired local or systemicphysiological or pharmacological effect; b) a unitary cup essentiallyimpermeable to the passage of said agent that surrounds and defines aninternal compartment to accept said drug core, said unitary cupcomprising an open top end and at least one lip around at least aportion of said open top end of said unitary cup; and c) a permeableplug permeable to the passage of said agent positioned at said open topend of said unitary cup wherein said lip interacts with said permeableplug holding it in position and closing said open top end, saidpermeable plug allowing passage of said agent out of said drug core,through said permeable plug, and out said open top end of said unitarycup.
 25. The method according to claim 24, wherein said inserting stepcomprises inserting said sustained release drug delivery device in alocation selected from a group consisting of the vitreous of the eye,under the retina, and onto the sclera.
 26. The method according to claim24, wherein said drug core contains a plurality of said agents.
 27. Themethod according to claim 24, wherein said inserting step comprisesinjecting said sustained release drug delivery device at the desiredlocation.
 28. A method of manufacturing a sustained release drugdelivery device comprising: a) manufacturing a drug core comprising atleast one agent effective in obtaining a diagnostic effect or effectivein obtaining a desired local or systemic physiological orpharmacological effect; b) providing a unitary cup essentiallyimpermeable to the passage of said agent that surrounds and defines aninternal compartment to accept said drug core, said unitary cupcomprising an open top end with at least one recessed groove around atleast some portion of said open top end of said unitary cup; c)inserting said drug core into said unitary cup; and d) filling amaterial which is permeable to the passage of said agent into said opentop end of said unitary cup, allowing said material to solidify therebyforming a permeable plug positioned at said open top end of said unitarycup wherein said groove interacts with said permeable plug holding it inposition and closing said open top end, said permeable plug allowingpassage of said agent out of said drug core, through said permeableplug, and out said open top end of said unitary cup.
 29. The method ofmanufacturing a sustained release drug delivery device according toclaim 28, wherein said drug core is manufactured as a solid dose form.30. The method of manufacturing a sustained release drug delivery deviceaccording to claim 28, wherein said drug core is manufactured as a soliddispersion.
 31. The method of manufacturing a sustained release drugdelivery device according to claim 28, comprising the further step ofcuring the assembled sustained release drug delivery device.
 32. Amethod of manufacturing a sustained release drug delivery devicecomprising: a) manufacturing a drug core comprising at least one agenteffective in obtaining a diagnostic effect or effective in obtaining adesired local or systemic physiological or pharmacological effect; b)providing a unitary cup essentially impermeable to the passage of saidagent that surrounds and defines an internal compartment to accept saiddrug core, said unitary cup comprising an open top end with at least onelip extending around at least a portion of the said open top end of saidunitary cup; c) inserting said drug core into said unitary cup; and d)filling a material which is permeable to the passage of said agent intosaid open top end of said unitary cup, allowing said material tosolidify thereby forming a permeable plug positioned at said open topend of said unitary cup wherein said lip interacts with said permeableplug holding it in position and closing said open top end, saidpermeable plug allowing passage of said agent out of said drug core,through said permeable plug, and out said open top end of said unitarycup.
 33. The method of manufacturing a sustained release drug deliverydevice according to claim 32, wherein said drug core is manufactured asa solid dose form.
 34. The method of manufacturing a sustained releasedrug delivery device according to claim 32, wherein said drug core ismanufactured as a solid dispersion.
 35. The method of manufacturing asustained release drug delivery device according to claim 32, comprisingthe further step of curing the assembled sustained release drug deliverydevice.